Cancer is one of the scourges of human existence. Although chemotherapeutic agents that are effective in treating malignant tumors are known, such agents generally cause severe side effects.
For example, brain cancer is generally associated with a particularly grim prognosis. The average survival rate from brain cancer is barely two years, and the entire therapeutic procedure of tumor resection followed by chemo- and/or radiation therapy is extremely painful and causes many side effects.
Curcumin is a component of the culinary ingredient turmeric, and has the chemical name 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione. Curcumin directly inhibits a group of active proteins and also indirectly modulates other crucial enzymes and transcription factors that promote tumor cell survival and proliferation. Being able to selectively inhibit a large number of cell cycle- and tumor-promoting proteins, it is likely that curcumin attacks cancer cells by simultaneously regulating multiple pathways. Spectroscopic analyses have shown that curcumin is taken up more rapidly by tumor cells and the amount of curcumin taken up by the cancer cells is directly proportional to cell death. (Kunwar, A., Batik, A., Mishra, B., Rathinasamy, K., Pandey, R., and Priyadarsini, K. I. Biochimica et Biophysica Acta (BBA)—General Subjects 1780, 673-679) (2008). Accordingly, curcumin is toxic to cancer cells, but is generally non-toxic to non-transformed cells. Purkayastha, S., Berliner, A., Fernando, S. S., Ranasinghe, B., Ray, I., Tariq, H., and Banerjee, P., Brain Research 1266C, 130-138 (2009); and Dhandapani, K. M., Mahesh, V. B., and Brann, D. W. J. Neurochem. 102, 522-538 (2007).
Although curcumin is harmless to most normal cells, its administration to humans is somewhat restricted by its poor solubility in water and also by its rapid metabolism in the body (Purkayastha, S., Berliner, A., Fernando, S. S., Ranasinghe, B., Ray, I., Tariq, H., and Banerjee, P., Brain Research 1266C, 130-138) (2009)). Various solubilized versions of curcumin (involving biocompatible solvents or incorporation into appropriate nanoparticles) have been prepared and such formulations are being tested currently. See Carter, Journal of the National Cancer Institute 100, 616-617 (2008); Singh, Cell 130, 765-768 (2007); and Purkayastha, S., Berliner, A., Fernando, S. S., Ranasinghe, B., Ray, I., Tariq, H., and Banerjee, P., Brain Research 1266C, 130-138 (2009).
Nevertheless, the administration of solubilized curcumin still leaves open the possibility of losing significant amounts of the injected curcumin through metabolic breakdown even before it reaches the target cancer cells. Consequently, reaching a high concentration of curcumin in the cancer cells remains difficult through such strategies.
State-of-the-art targeting antibodies are also known. Such antibodies are capable of directing chemotherapeutic drugs to tumor cells. If made in mammals other than humans, targeting antibodies can be humanized. Alternatively, human antibodies developed using transgenic mice and phage display are also known (McCafferty et al., Nature 348, 552-554 (1990); Lonberg, N. Nat Biotech 23, 1117-1125 (2005); Reichert et al., Nature Biotechnology 23, 1073-1078 (2005); Senter, P. D. Current Opinion in Chemical Biology 13, 235-244 (2009); and Reichert et al., Nature Reviews. Drug Discovery 6, 349-356 (2007)).
However, cancer researchers generally use antibody-mediated targeting only if the anticancer agent is toxic toward normal cells. For example, the increasing use of targeted anticancer agents that inhibit tyrosine kinase signaling (monoclonal antibodies or tyrosine kinase inhibitors) (trastuzumab, sunitinib) has dramatically improved the survival of patients with malignancies, but cardiotoxicity, including heart failure, left ventricular dysfunction, hypertension, myocardial infarction, and thromboembolism, has accompanied such treatment (Chen, Current Cardiology Reports 11, 167-174 (2009).)
Similarly, other anticancer agents currently used or being developed for antibody targeting such as maytansinoids, calicheamycin, or auristatins (Fennell et al., J. Antimicrob. Chemother. 51, 833-841 (2003)); Tassone et al., Blood 104, 3688-3696 (2004); and Tassone et al., Cancer Res 64, 4629-4636 (2004) belong to this category in which the untargeted form of each drug is toxic toward normal cells (Ikeda et al., Clinical Cancer Research 15, 4028-4037 (2009); van der Velden, et al., Blood 97, 3197-3204 (2001); and Law et al., Clinical Cancer Research 10, 7842-7851 (2004)). Consequently, it is difficult to eliminate the side effects of these targeted agents at higher doses, which are often required in aggressive treatment of cancer.